Alzheimer's disease (AD) is the main cause of dementia in the elderly. Its increasing prevalence and enormous cost threaten the health and economic stability of people in the United States and many other nations. Thus, there is an urgent need to deepen our understanding of this illness and to develop better strategies to treat and prevent it. In this project, we use transgenic (tg) mouse models to study the roles of amyloid proteins and apolipoprotein (apo) E in the pathogenesis of AD. During the last funding cycle, we overexpressed human amyloid protein precursors (APPs) and APP-derived amyloid peptides (Ap)in neurons of tg mice. Similar to people with AD, APP mice showed progressive deposition of Ap in amyloid plaques and degeneration of neurons and synapses. Plaque formation depended not only on absolute levels of the fibrillogenic AfH-42 peptide but also on a number of key modifiers. High A|3l-40/Apl-42 ratios and ablation of apoE prevented neuritic plaques, whereas a,-antichymotrypsin doubled the plaque load. The cytokine transforming growth factor pi had complex effects, decreasing the overall plaque burden while promoting amyloid deposition in blood vessels. Synaptic deficits correlated with AP levels but not with plaque load, suggesting a plaque-independent role for AP in AD. Expression of apoES, but not of apoE4, prevented or delayed synaptic deficits and memory impairments in APP/apoE doubly tg mice, consistent with observations by others that apoE4 increases AD risk, accelerates AD onset, and is found in the majority of people with AD. This application follows up on our previous results, extends our project from AD pathogenesis to treatments, and addresses several important unanswered questions. We propose to determine whether nondeposited forms of AP such as Ap-derived diffusible ligands (ADDLs) cause the plaque- independent neurohal deficits we identified in APP tg mice; whether these deficits can be prevented and ameliorated by vaccination with ADDLs; whether apoE3 suppresses ADDLs more effectively than apoE4 in APP/apoE mice, tg glial cultures, and cell-free conditions; and whether transient expression of apoE3 in adult regulatable APP/apoE mice can decrease ADDL levels and inhibit neuronal deficits. We also propose to use DNA microarrays to identify additional mechanisms by which apoE isoforms might affect AP/ADDL- induced neuronal deficits. Achieving these aims could shed light on the molecular pathways that culminate in AD-associated cognitive decline and assist in the preclinical evaluation of novel treatments for the most common neurodegenerative disorder.